Huntington's disease (HD) is the most common inherited neurodegenerative disorder caused by an expanded DNA trinucleotide CAG in the Huntingtin gene. The clinical diagnosis of HD is based on the presence of movement disorders. However, subtle-to-prominent brain functional changes can precede by years the motor- based onset. Given the availability of a genetic testing, it is possible to identify which subjects will develop the disease before motor symptoms are present. This provides a unique opportunity to identify potential biomarkers, which would be of unquestionable value for promoting the development of disease-modifying therapies. To date, proven neuroprotective strategies for HD remain elusive although there has been a rapid progress in understanding of the pathogenesis. Part of the problem is that most of the clinical trials have attempted intervening when the degenerative process is already advanced making it difficult even for the most effective therapy to demonstrate any benefit. Thus, availability of sensitive biomarkers during the premanifest phase is critical for determining an optimal time to initiate the treatment, as well as for reliably evaluating efficacy in clinical trials. The brain is an energy-demanding organ that weighs ~2% of the whole body but consumes ~20% of total body glucose in the resting state. Strong evidence of early glucose hypometabolism in the HD brain has been reported. Whether glucose hypometabolism in premanifest HD represents an irreversible damage or whether it predicts the brain structural changes remains unknown. Glucose uptake in brain has been assessed mostly using 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography. Glucose chemical exchange saturation transfer (glucoCEST) MRI is a recently developed technique that can detect unlabeled glucose at physiologically relevant concentrations using proton-only MRI scanners without the requirement of additional hardware. This new method allows the detection of low concentration glucose through the chemical exchange of protons between hydroxyl groups and water. However, the sensitivity of the conventional glucoCEST MRI is limited due to the fast-exchange rates of these hydroxyl protons (>3000 Hz). In order to improve the labeling efficiency of such protons, we recently developed an on-resonance variable delay multiple pulse (onVDMP) MRI sequence. Our preliminary data show an exciting discovery, namely that this technique is sensitive to differentiate the glucose uptake and clearance in HD mouse brain from controls. The objective of this R21 is to determine whether onVDMP MRI measures of glucose uptake can serve as sensitive biomarkers for characterizing early disease progression and assessing response to treatment in HD mice. In Aim 1, we will identify spatiotemporal dynamics of glucose uptake and clearance in HD mouse brain and to determine whether impaired glucose uptake and clearance progresses with disease and predates and predicts selective brain atrophy, as measured by high-resolution MRI. In Aim 2, we will assess whether facilitating glymphatic function will improve glucose uptake and clearance in the HD mouse brain.